The parkinsonism-associated protein FBXO7 cooperates with the BAG6 complex in proteasome function and controls the subcellular localization of the complex

Abstract

The regulation of proteasome activity is essential to cellular homeostasis and defects have been implicated in various disorders including Parkinson disease. The F-box protein FBXO7 has been implicated in early-onset parkinsonism and has previously been shown to have a regulatory role in proteasome activity and assembly. Here, we report the association of the E3 ubiquitin ligase FBXO7-SCF (SKP1, cullin-1, F-box protein) with the BAG6 complex, consisting of the subunits BAG6, GET4 and UBL4A. We identify the subunit GET4 as a direct interactor of FBXO7 and we show that the subunits GET4 and UBL4A are required for proper proteasome activity. Our findings demonstrate reduced binding of FBXO7 variants to GET4 and that FBXO7 variants bring about reduced proteasome activity. In addition, we find that GET4 is a non-proteolytic substrate of FBXO7, that binding of GET4 to BAG6 is enhanced in the presence of active FBXO7-SCF and that the cytoplasmic localization of the BAG6 complex is dependent on the E3 ubiquitin ligase activity. Taken together, our study shows that the parkinsonism-associated FBXO7 cooperates with the BAG6 complex in proteasome function and determines the subcellular localization of this complex.

Genome-wide CRISPR/Cas9 screen shows that loss of GET4 increases mitochondria-endoplasmic reticulum contact sites and is neuroprotective

“…However, the GET4 gene has altered poly(A) site usage as a result of WT tau [ 74 ], a protein known to make fibrils in AD, that can bind disease-causing fragments of TDP-43 219 and contribute to ALS [ 75 ]. Furthermore, GET4 and BAG6 can interact with FOBOX7, a PD-causing gene [ 76 ], suggesting that GET4 can be linked to neurodegeneration, but its role in MERCS modulation is unknown. Future work is needed to determine if the expression levels of either GET4 or BAG6 , as well as potential DNA variants in their coding sequences that alter their biological activity are linked to neurodegeneration in humans.…”

A sporadic Parkinson’s disease model via silencing of the ubiquitin–proteasome/E3 ligase component, SKP1A

“…However, SKP1 function in neuronal cells is unknown. Recently, two separate findings provided significant support to the existence of a functional relation between Skp1 and brain degeneration in mammals: (1) The identification of parkinsonism-causing mutations in PARK15 / FBXO7 (Di Fonzo et al 2009 ; Randle and Laman 2017 ; Wang et al 2021 ), a Skp1-interacting protein belonging to the family subgroup of F-box domain only (Fbxo) proteins (Dabool et al 2020 ). The mutations have been found to cause autosomal recessive early onset parkinsonism.…”